The lethal doses (LD-10 days) for combinations of salts of lead (acetate), mercuric (chloride), and cadmium (chloride) were determined following intravenous injection in SPF Wistar male rats (190-210 grams). A rapid, simplified experimental procedure of general applicability has been developed by which the combined effects of toxic agents are determined, yielding a complete mortality curve. This threshold dose method (TDM), also provides a simple test for additivity, antagonism, and synergism. When combinations of substances are tested by the TDM, all substances except one are fixed at their known combined (LDO)t where t equals threshold i.e., the maximum non-lethal dose just preceeding a measurable response to further doses of the single incremented substance. For pairs of the metal combinations, three were antagonistic (protective), one additive, and two synergistic. The combination, Hg/plus Pb, was unusually synergistic. Experiments on all combinations of triplets are being completed, e.g., Hg plus Pb/plus Cd. Results are explicable by a model involving blocking of metal-binding sites in and on the cell. The potential practical significance of these findings and the TDM, as well as extension of these studies to cytogenetic effects and mixed chelant therapy are discussed.